This proposal deals with tumor metastasis. Cancer cells disseminate to distant sites in the body through lymphatic and blood circulation. The factors that determine the entry of malignant cells into blood vessels, their ability to survive the passage through them and their ultimate destination are obviously of great interest for the understanding of cancer biology and for the eventual control of cancer. Working with integrins and their extracellular matrix ligands in tumor cells, we have discovered new leads that may help understand some of these factors. We have designed a polymeric form of fibronectin, sFN, that appears to facilitate the elimination of tumor cells from the circulation and may also change their tissue destination. These findings have led us to hypothesize that normal plasma fibronectin may play a similar role, serving as an innate anti-cancer defense system. This application proposes studies designed to test these hypotheses. These studies will provide significant new information on the biology of cancer metastasis and the fate of other tissue cells in the circulation. The biological mechanisms to be elucidated here may advance sFN toward clinical use. Finally, the ability to eliminate tumor cells from the circulation by sFN administration may provide additional protection against tumor cell transfer in bone marrow transplantation used to treat cancer and against tumor metastasis.